This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. According to the world health organization HIV is the number one cause of human morbidity and mortality worldwide. The increased use of highly active antiretroviral therapy in the developed world has resulted in a decrease in morbidity and increase in survival of HIV infected individuals. One consequence of this increased survival is the emergence of new tissue specific manifestations of HIV infection, including pulmonary arterial hypertension. Pulmonary complications of chronic HIV infection are now being recognized with increasing frequency. Currently the pathogenesis of HIV pulmonary arteriopathy is poorly understood, limiting the development of both treatment and prevention strategies. There are numerous limitations in understanding of the relationship between HIV and the development of pulmonary hypertension in humans. These include difficulty in making serial measurements of cardiac and pulmonary function over the natural course of infection, the use of illicit drugs or agents that may be cardiotoxic. Prior studies have shown that rhesus macaques infected with SHIV-nef which is a chimeric viral construct containing the HIV nef gene in a Simian immunodeficiency virus backbone developed complex plexiform [unreadable]like pulmonary arterial lesions similar to those see in HIV associated pulmonary hypertension. In contrast, rhesus macaques infected with a non-chimeric Simian immunodeficiency virus (SIV) did not develop pulmonary arterial lesions similar to those occurring in HIV infected individuals. These findings suggest that the nef gene plays a key role in the development of this life threatening condition. The aim of this study is to try to elicit the cellular mechanisms by which the HIV nef gene induces complex pulmonary artery disease. We hope that by understanding the mechanisms involved in the development of pulmonary vascular disease in SHIV-nef infected macaques that both treatment and prevention strategies for this syndrome can be developed.